1. Field of the Invention
This invention relates to novel polypeptides having DNA binding activity, and to nucleic acid molecules encoding the polypeptides. The polypeptides, previously referred to as "IRF-3" polypeptides, are now referred to as "LSIRF" polypeptides (lymphocyte specific interferon regulatory factor), and are new members of the class of polypeptides known as interferon regulatory factors.
2. Description of Related Art
Regulation of gene expression can occur at several different levels, but the activation of gene-specific transcription factors is considered the most fundamental to this process. One family of transcription factors, the interferon regulatory factors (IRFs), consists of four members: IRF-1, IRF-2, ISGF3.gamma., and ICSBP. All four IRFs are characterized by a strongly conserved, N-terminal DNA-binding domain containing a repeated tryptophan motif (Veals et al., (Mol. Cell. Biol., 12:3315-3324 1992!).
Interferon regulatory factors-1 (IRF-1) and -2 (IRF-2) were originally identified by studies of the transcriptional regulation of the human interferon-beta (IFN-.beta.) gene (Miyamoto et al., Cell, 54:903-913 1988!) and (Harada et al., Cell, 58:729-739 1989!). cDNA expression studies have demonstrated that IRF-1 functions as a transcriptional activator of IFN and IFN-inducible genes, whereas IRF-2 represses the effect of IRF-1 (Fujita et al., Nature, 337:270-272 1989!) and (Harada et al., Cell, 63:303-312 1990!). Recent analyses have shown that IRF-1 can also act as a tumor suppressor gene and IRF-2 as a possible oncogene (Harada et al, Science, 259:971-974 1993!). IRF-1 expression is induced by type-I (.alpha./.beta.) and type-II (.gamma.) IFNs (Miyamoto et al., Cell, 54:903-913 1988!; Kanno et al., Mol. Cell Biol., 13:3951-3963 1993!), whereas IRF-2 is both constitutively expressed and induced by type-I IFNs (Harada et al., Cell, 58:729-739 1989!).
Interferon-stimulated gene factor-3 gamma (ISGF3.gamma.) is an IFN-.gamma.-inducible protein which associates with ISGF3.alpha. subunits activated from a latent cytosolic form by type-I IFNs (Levy et al, EMBO J., 9:1105-1111 1990!; Levy et al., New Biologist, 2:383-392 1990!). Upon association, this complex has been shown to translocate to the nucleus and bind a specific DNA sequence found in the promoter region of IFN-inducible genes, known as the ISRE (IFN-stimulated response element; Veals et al., Mol. Cell. Biol., 12:3315-3324 1992!). Recently, ISGF3.alpha. subunits of 91/84 kDa and 113 kDa have been cloned (Schindler et al, Proc. Natl. Acad. Sci. USA, 89:7836-7839 1992!; Fu et al, Proc. Natl. Acad. Sci. USA, 89:7840-7843 1992!) and designated as signal transducer and activator of transcription-1 (Stat-1) and -2 (Stat-2), respectively, which are targets of JAK kinase phosphorylation following type-I IFN/IFN-receptor engagement (Shuai et al, Science, 261:1744-1746 1993!; Darnell et al, Science, 261:1415-1421 1994!).
Interferon consensus sequence binding protein (ICSBP) is also an IFN-.gamma.-inducible protein, originally isolated as a protein that recognizes the ISRE motif (also called ICS) of the promoter of murine MHC class I, H-2L.sup.D gene (Driggers et al, Proc. Natl. Acad. Sci. USA, 87:3743-3747 1990!). However, unlike IRF-1, IRF-2, and ISGF3.gamma., ICSBP exhibits a tissue-restricted pattern of expression, as it is induced exclusively in cells of macrophage and lymphoid lineages (Driggers et al, Proc. Natl. Acad. Sci. USA, 87:3743-3747 1990!). Recent studies have suggested that ICSBP has a similar role to IRF-2 in antagonizing the effect of IRF-1 on the induction of IFN and IFN-inducible genes (Weisz et al., J. Biol. Chem., 267:25589-25596 1992!; Nelson et al., Mol. Cell. Biol., 13:588-599 1993!). The ISREs of interferon-inducible genes overlap IRF-E, the DNA sequences recognized by IRF-1 and -2 (Tanaka et al., Mol Cell. Biol. 13:4531-4538 1993!). Very recently, ISGF3.gamma. was shown to bind the IRF-Es of the IFN-.beta. gene (Kawakami et al., FEBS Letters, 358:225-229 1995!).
In view of the importance of IRFs in regulating the expression of the interferon genes and other genes, there is a need in the art to identify other IRFs, especially tissue specific IRFs.
Accordingly, it is an object of this invention to identify novel members of the IRF gene family.
Other objects will be readily apparent to one of ordinary skill in the art.